The broad overall objective of this research is to enhance drug delivery to the anterior segment of the eye. More specifically the goal of this research is to develop acycloguanosine analogues of greater efficacy and reduced toxicities in the treatment of necrotising herpes simplex and cytomegalovirus macular and peripheral iritis, uveitis and retinitis in AIDS patients. Acycloguanosine analogues have low thermodynamic activity or escaping tendency from the aqueous phase into the lipid biophase. The specific aim will be achieved via the synthesis of a series of lipophilic bioreversible analogues. A series of 3', 5'-diesters of ganciclovir and 3'-monoesters of acyclovir will be synthesized comprising of 1) a homologous series of aliphatic esters: propionate, butyrate and valerate, 2) branched chain aliphatic esters: pivaloate, isobutyrate, 3) aromatic esters: benzoate, p- methoxy, p-nitro benzoates and 4) alicyclic ester: 1-adamantoate. The compounds are purified by recrystallization from methanol-chloroform mixture and purity is checked by HPLC. TLC and by melting point on two successive crystallizations. Characterization of these compounds will be made with respect to their I.R., N.M.R., mass spec. melting points, aqueous solubilities and octanol/water partition coefficients. The in-vitro kinetics of chemical and enzymatic regeneration of the parent drugs will be studied using appropriate media and tissue homogenates. Evaluation of the rates of permeation across the rabbit corena will be made. The transfer, disposition and bioconversion of these compounds from both topical and intravitreal delivery will also be defined. These novel prodrugs are expected to permeate more rapidly and to a greater extent into the ocular tissues and nerve cells than parent acyclovir or ganciclovir. The pharmacokinetic and disposition characteristic studies of the analogues will result in the identification of a compound with optimal therapeutic potential. the distribution of the esters, regenerated parent drug and any phosphate metabolite in the plasma, aqueous humor, cornea, lens, iris- ciliary body, vitreous and retinal tissues will be measured at (1) at different time points following topical administration of 50 micro1 volume of the same molar concentration of each compound (2) at different time points following intravitreal injection of the same molar equivalent doses of all compounds. Preliminary experiments just performed in our laboratory revealed that 50 microL of a 1mM topical dosing of acyclovir-3'-valerate produced an aqueous humor acyclovir level of 25.99 microM at 30 mins post instillation compared to 6.25 microM concentration from a molar equivalent dose of the parent drug acyclovir. The parent drug is the only chemical species observed in the ocular fluids at 30 mins following topical dosing of the 3'-valerate analogue. The antiviral efficacies of three pharmacokinetically optimized analogues in each series (acyclovir and ganciclovir) will be evaluated in virus infected rabbit acute epithelial keratitis models by Prof. James Hill at LSU Eye Center. LSU Medical Center, New Orleans, Louisiana. The unsacrified corneas will be inoculated with 25micro1 of a suspension of HSV-1 strain McKrae (1x10(5) Plaque Forming Units/ml. The lesions after infections and after topical dosing of 50 micro1 solution of 1mM derivative will be evaluated by Slit-Lamp Biomicroscopic Examination.